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Dietary phytoestrogen intake and premenopausal breast cancer risk in a german case-control study

Int. J. Cancer: 110, 284 –290 (2004)
Publication of the International Union Against Cancer
DIETARY PHYTOESTROGEN INTAKE AND PREMENOPAUSAL BREASTCANCER RISK IN A GERMAN CASE-CONTROL STUDY
INSEISEN ,* Regina PILLER , Silke HERMANN and Jenny CHANG-CLAUDE
1Unit of Human Nutrition and Cancer Prevention, Technical University of Munich, Freising-Weihenstephan, Germany2Department of Clinical Epidemiology, Deutsches Krebsforschungszentrum, Heidelberg, GermanyA diet high in isoﬂavonoids (soy) is associated with lower
In Western populations with a low intake of isoﬂavonoids,
breast cancer risk in Asian populations. Due to the low soy
dietary intake of another class of phytoestrogens, lignans, may be
intake, dietary lignans may be the more important phy-
more important. Lignans, mainly secoisolariciresinol and mataires-
toestrogen class in Western populations. We used a popula-
inol, are more widespread in plants and plant products (e.g., whole
tion-based case-control study of breast cancer by age 50 in
grains, berries) that are frequently included in the usual Western
southern Germany to evaluate the association between di-etary intake of different phytoestrogens and premenopausal
diet.14,15 Analytic data for the lignan content of an acceptable
breast cancer risk. Dietary information was collected from
range of foodstuffs have become available only recently, so few
278 premenopausal cases and 666 age-matched controls, us-
studies on the effect of lignan intake on breast cancer risk have
ing a validated FFQ. Using multivariate logistic regression,
been performed.16,17 Additionally, lignans undergo bacterial me-
the highest vs. lowest intake quartiles of daidzein and
tabolism in the human intestine, and only their metabolites entero-
genistein yielded signiﬁcantly reduced ORs (95% CI) for
diol and enterolactone are able to pass the intestinal barrier to exert
breast cancer risk of 0.62 (0.40 – 0.95) and 0.47 (0.29 – 0.74),
biologic effects.18,19 Studies using enterolactone concentrations as
respectively. The protective effects of daidzein and genistein
biomarkers of lignan intake (and intestinal microbial activity) have
were found only for hormone receptor-positive tumors. High
given conﬂicting results: an inverse association with breast cancer
intake of other isoﬂavonoids, e.g., formononetin and biocha-nin A, as well as the sum of isoﬂavonoids were not associated
risk was found in 3 case-control studies,20–22 but no clear answer
with a decrease in risk. Breast cancer risk signiﬁcantly de-creased with a high intake of the plant lignan matairesinol
Therefore, our aim was to assess the association of dietary
(OR ؍ 0.58, 95% CI 0.37– 0.94) but not secoisolariciresinol or
intake of different phytoestrogens with premenopausal breast can-
the sum of plant lignans. However, both estimated mamma-
cer risk in a German study population with a Western lifestyle, also
lian lignans, enterodiol and enterolactone, were inversely
considering the hormone receptor status of breast cancer tissue. In
associated with breast cancer risk, with ORs (95% CI) of 0.61(0.39 – 0.98) and 0.57 (0.35– 0.92), respectively. No effect was
addition, the bioavailable intestinal lignan metabolites enterodiol
found for total phytoestrogen intake. Our results suggest an
and enterolactone were calculated and related to breast cancer risk.important role of dietary intake of daidzein and genistein,despite low levels, as well as of matairesinol and mammalianlignans to reduce premenopausal breast cancer risk in thisstudy population.2004 Wiley-Liss, Inc.
Participants in our population-based case-control study were
recruited in the 2 study areas of Freiburg and Rhein-Neckar-
Key words: dietary intake; phytoestrogen; isoﬂavonoid; plant lignan;
Odenwald between January 1992 and December 1995. All Ger-
mammalian lignan; breast cancer; premenopausal women
man-speaking women who were not older than 50 years at the timeof diagnosis of incident in situ or invasive breast cancer wereeligible. Patients were identiﬁed by frequent monitoring of hospital
By deﬁnition, phytoestrogens are secondary plant components
admissions, surgery schedules and pathology records of 38 hospi-
that show structural similarity to mammalian estrogens and, there-
tals. Among the 1,020 eligible patients in both study regions, 706
fore, are able to bind to mammalian estrogen receptors.1 Of the 3
(70.2%) completed the study questionnaire. Controls matched by
main classes, isoﬂavonoids, lignans and coumestanes, the isoﬂa-
exact age and study region were selected from a random list of
vonoids, namely daidzein and genistein, have received the most
residents derived from the population registries. Of the 2,257
scientiﬁc attention in the last years due to their suggested health
eligible controls, 1,381 (61.2%) participated in the study.25,26 The
effects.2,3 Daidzein and genistein are found in high concentrationsin soybeans. Consequently, in Asian populations with a fairly highintake of soy and soy products, isoﬂavonoid intake might be high
Abbreviations: BMI, body mass index; CI, conﬁdence interval; EPIC,
enough to reveal biologic effects in humans.4 Soy consumption has
European Prospective Investigation into Cancer and Nutrition; FFQ, food-
been suggested to contribute to the lower prevalence of breast
frequency questionnaire; FSH, follicle-stimulating hormone; LH, luteiniz-
cancer in Asian compared to Western populations.5,6 Since estro-
ing hormone; OR, odds ratio; SHBG, sex hormone– binding globulin.
gen levels affect breast cancer,7 the early postulated anticarcino-genic mechanism is based on the weak estrogen-like activity
Grant sponsor: Kurt-Eberhard-Bode-Stiftung; Grant sponsor: Deutsche
(compared to endogenous estrogen) of genistein and, to a lesser
extent, daidzein, as found in in vitro studies.1,8,9 These substanceshave since been shown to have hormonal receptor-independentanticarcinogenic effects in cancer cell lines and animal studies,
*Correspondence to: Unit of Human Nutrition and Cancer Prevention,
such as inhibition of angiogenesis, effects on endogenous hormone
Technical University of Munich, Alte Akademie 16, 85350 Freising-
concentrations and metabolism as well as antioxidant activity.10–12
Weihenstephan, Germany. Fax: ϩ49-8161-713931.
Stimulatory effects on carcinogenic processes as observed in invitro studies were not found in vivo.10
According to previous reviews,10,13 analytic epidemiologic stud-
Received 4 August 2003; Revised 30 October 2003; Accepted 10
ies in humans support the view of a protective effect of soy
consumption or related phytoestrogen intake on breast cancer riskwhen consumed at an early age (adolescence) or at very high
doses. So far, only few investigations have been conducted in
Published online 26 February 2004 in Wiley InterScience (www.
study was approved by the local ethical committee, and all partic-
and total physical activity did not affect the estimates signiﬁcantly
and, thus, were not used for adjustment. For trend estimation,
Both cases and controls ﬁlled in a self-administered risk factor
categorized variables were entered into the regression models as
questionnaire, collecting information on demographic factors, an-
thropometric measures, menstrual history, reproductive history,breast-feeding history, family history of cancer, smoking history
and alcohol consumption. If not otherwise speciﬁed, all informa-tion was truncated at the reference date, which was the date of
A total of 278 cases and 666 controls were classiﬁed as pre-
diagnosis for cases and the date of questionnaire completion for
menopausal at the time of diagnosis (cases) or recruitment (con-
controls. Menopausal status was assigned according to the reported
trols) and were, therefore, included in the evaluation. A description
state half a year before the reference date. The menopausal status
of sociodemographic variables and known risk factors for breast
of women with previous hysterectomy not accompanied by bilat-
cancer is given in Table I. The mean age for cases and controls was
eral oophorectomy was not identiﬁable and classiﬁed as unknown.
42.6 years (SD Ϯ5.48, Ϯ5.77, respectively). Total daily energy
Information on hormone receptor status (estrogen, progesterone)
intake was signiﬁcantly different between cases and controls (Ta-
of breast cancer tissue was obtained from pathology reports.
In addition, participants from Rhein-Neckar-Odenwald were
Median dietary intake of phytoestrogens in cases and controls is
asked to complete a self-administered FFQ, recording nutritional
given in Table II. The higher intake of genistein among controls
habits in the year prior to the diagnosis of breast cancer (cases) or
compared to cases was statistically signiﬁcant. Additionally, cases
questionnaire completion (controls). The FFQ, consisting of 176
and controls differed signiﬁcantly in formononetin intake. For all
food items, is comparable to the FFQ used for the German part of
other phytoestrogens, no signiﬁcant differences existed. Secoiso-
the EPIC study; it was validated for food group, energy and
lariciresinol contributed nearly 50% of total phytoestrogen intake
nutrient intake.27,28 A detailed description of this FFQ, including
of about 1,000 ␮g/day. Relevant food sources for different phy-
the treatment of missing values, was published previously.29 The
toestrogens are listed in Table III.
FFQ was returned by 1,288 of the 1,451 participants from Rhein-
Except for genistein (4th vs. 1st quartile), formononetin and
Neckar-Odenwald (88.8%). The median time between diagnosis
biochanin A (3rd vs. 1st quartile), none of the crude estimates for
and FFQ administration was 209 days for patients. Patients who
breast cancer risk was statistically signiﬁcant (Table IV). After
ﬁlled in the FFQ more than 2 years after diagnosis were excluded
adjustment for several risk factors for breast cancer and possible
from analysis. Information about portion size and frequency of
confounders, high intake of daidzein and genistein was inversely
consumption for single food items was used to calculate mean food
associated with premenopausal breast cancer risk (Table IV). For
intake per day. Nutrient intake was computed by means of the
the sum of daidzein and genistein, the risk estimates for both the
German food composition table BLS II.3 (Bundesinstitut fu¨r ge-
3rd and 4th intake quartiles were signiﬁcantly decreased compared
su˘ndheitlichen Verbraucherschu¨tz und Veterina¨rmedizin, Berlin,
to the lowest intake category, with ORs (95% CI) of 0.63 (0.41–
Germany). Food items were classiﬁed into 14 groups.29 After
0.96) and 0.56 (0.36 – 0.87), respectively (p
exclusion of the top and bottom 1% of the energy intake range
formononetin and biochanin A was associated with increased
(extreme over- and underreporting), 355 cases and 838 controls
breast cancer risk in the 3rd intake quartile but not the 4th quartile;
were ﬁnally included in the analyses.
overall, no signiﬁcant effect was found for the sum of isoﬂa-
To estimate dietary phytoestrogen intake, a database of phy-
vonoids (Table IV). Coumestrol intake was also not associated
toestrogen-containing foods was established using the available
analytic data from the literature, focusing on foodstuffs usually
Of the lignans, no effect was found for secoisolariciresinol.
consumed in Europe.2,14,30–40 The food content of the isoﬂa-
However, premenopausal breast cancer risk decreased with in-
vonoids (daidzein, genistein, formononetin, biochanin A), coumes-
creasing intake of matairesinol (OR ϭ 0.58, 95% CI 0.37– 0.94 in
tanes (coumestrol) and lignans (secoisolariciresinol, matairesinol)
4th vs. 1st intake quartile, p
was included as aglycons in micrograms per 100 g edible food
derived phytoestrogens did not affect breast cancer risk. A high
portion. If more than one value for the same foodstuff was avail-
estimated amount of mammalian lignans, enterodiol and enterolac-
able, mean values were calculated. Additionally, in vitro data on
tone, was inversely associated with breast cancer risk. ORs (95%
the intestinal production of enterodiol and enterolactone after
CIs) for the highest vs. lowest quartile were 0.61 (0.39 – 0.98,
incubation with human feces were used to estimate the bioavail-
ϭ 0.034) for enterodiol and 0.57 (0.35–0.92, p
able intestinal lignan metabolites per 100 g of food ingested.41
When a particular phytoestrogen was found “in trace amounts” in
If considering only patients who completed the FFQ within 1
a certain food, it was assigned to 0.01 ␮g/100 g food. After
year after diagnosis (n ϭ 213), adjusted relative risks were only
calculation of the phytoestrogen content of each FFQ item, mean
slightly modiﬁed with few exceptions: relative risk estimates for
daily intake of the different phytoestrogens was computed for each
the 3rd quartiles of daidzein intake and total isoﬂavonoid intake
became signiﬁcant, while for matairesinol, enterodiol and en-
The association between phytoestrogen intake and risk of pre-
terolactone the point estimates for the 4th intake quartiles slightly
menopausal breast cancer was estimated by means of conditional
increased, with ORs of 0.64, 0.66 and 0.63, but were no longer
logistic regression modeling. ORs and their corresponding 95%
CIs were calculated using the PHREG procedure of the SAS
We also examined the combined effect of daidzein and genistein
statistical software package, version 8.2 (SAS Institute, Cary, NC)
intake and intestinal lignan metabolites. Women were grouped by
with stratiﬁcation for exact age. Higher quartiles of phytoestrogen
low (1st and 2nd quartiles) and high (3rd and 4th quartiles)
consumption were compared to the lowest quartile of consump-
consumption of daidzein and genistein and of enterodiol and
tion, whereby the distribution of the phytoestrogen intake in con-
enterolactone. High consumption of both phytoestrogen classes
trols was used for quartile deﬁnition. Results were adjusted for
showed the strongest risk reduction, with an adjusted OR (95% CI)
ﬁrst-degree family history of breast cancer (no, yes), number of
of 0.57 (0.36 – 0.83) compared to low consumption of both groups
births (3 categories of 0, 1 or 2, Ն3), duration of breast-feeding (4
categories of 0, 1– 6, 7–12, Ͼ12 months), energy intake (deciles),
Further, we examined whether the phytoestrogen effect differed
BMI [classiﬁed as underweight (Ͻ18.5 kg/m2), normal weight
by hormone receptor status. Differentiated by estrogen and pro-
(18.5–30 kg/m2) and obese (Ն30 kg/m2)], education level (low,
gesterone receptor status of breast tissue, a signiﬁcant inverse
middle, high) and alcohol consumption (3 categories of 0, 1–18
association between daidzein and genistein intake and breast can-
and Ͼ18 g ethanol/day). Age at menarche, smoking, sports activity
cer risk was found only for breast tumors positive for estrogen or
TABLE I – DISTRIBUTION OF SOCIODEMOGRAPHIC VARIABLES AND RISK
The observed effects of genistein and daidzein were largely
FACTORS FOR PREMENOPAUSAL BREAST CANCER IN CASES (N ϭ 278)
unexpected because the intake levels for these compounds are very
low (150 –160 ␮g/day) compared to Asian populations (10 –30
mg/day).4 Concentrations necessary to reveal hormone receptor–
mediated effects as determined in in vitro studies are unlikely to bereached by the estimated dietary intake range in this study popu-
lation. This suggests a hormone receptor-independent mechanism
of action of these isoﬂavonoids, which, however, appears to be
contradicted by the clear results showing that the genistein and
daidzein effects are restricted to hormone receptor-positive tumors.
Isoﬂavonoid effects on hormonal status and hormone metabolism
may help explain the ﬁndings. Besides in vitro results, human
intervention studies in premenopausal women and in men have
found a decrease in plasma 17␤-estradiol, progesterone, FSH and
LH and an increase in plasma SHBG concentrations after admin-
istration of soy (isoﬂavonoids) or ﬂaxseed (lignans).11,19,42–44 In
addition, some studies have also shown increased ratios of urinary
2-(OH) to 16␣-(OH) and 2-(OH) to 4-(OH) estrogens associated
with soy intake.11 The latter ﬁnding suggests reduced formation of
genotoxic and potentially carcinogenic estrogen metabolites. Sev-
eral enzymes involved in estrogen metabolism can be affected
(mainly inhibited) by phytoestrogens, including aromatase and
sulfotransferases.12 The effects were less pronounced in postmeno-
pausal women.45 Thus, our present ﬁndings are compatible with
the biologic mechanisms showing an important role for isoﬂa-
vonoids in protecting against hormone-dependent breast cancer
through their effects on the generation, transport and removal of
endogenous steroid hormones; furthermore, some of these actions
are mediated by hormonal receptors and therefore dependent on
receptor status. Surprisingly, intake of formononetin and biochanin
A as precursors of daidzein and genistein was unrelated to breast
cancer risk or even increased risk (3rd quartile, Table IV). This
may indicate very limited conversion of these precursors to their
In contrast to daidzein and genistein, the protective effect found
for enterodiol and enterolactone was not modiﬁed by hormone
receptor status. This implies that there may be differences between
the 2 classes of phytoestrogens regarding the biologic mechanisms
involved in reducing breast cancer risk. Isoﬂavonoids and mam-
malian lignans show similar effects, such as competition with
estrogen for binding to estrogen receptors (type II), induction of
SHBG, inhibition of some steroid-metabolizing enzymes (aro-
matase) and antioxidant activity.1,18 However, depending on the
test systems used, differences between phytoestrogenic com-
pounds have been reported. The possible underlying mechanism
for the observed difference warrants investigation.
Two reviews dealing with the health effects of phytoestrogens
concluded that protective effects on breast cancer risk might be
found in women who consume soy phytoestrogens at an early age
(adolescence) or at very high doses.10,13 Most of the included
studies evaluated the relationship between intake of soy/soy prod-
ucts and disease risk, predominantly in Asian populations. Studies
which assessed isoﬂavonoid or lignan metabolite concentrations in
plasma or urine samples in relation to breast cancer yielded incon-
MET, metabolic equivalents; data available for 187 cases and 525
sistent results. While 2 prospective studies failed to ﬁnd a signif-
icant inverse association between high urinary isoﬂavonoid excre-tion or serum enterolactone concentrations and breast cancer
progesterone receptor (Table VI). The effects of enterodiol and
risk,23,24 5 case-control studies reported a protective effect on
enterolactone were independent of hormone receptor status (data
Two studies in Asian populations, living in Japan (prospective
study)48 and the United States (case-control study),49 that assessed
overall isoﬂavonoid intake reported an inverse association with
We found a protective effect of a high intake of genistein and
breast cancer risk. The effect of dietary intake of isoﬂavonoids and
daidzein (isoﬂavonoids) and matairesinol (lignan) on breast cancer
lignans on breast cancer risk has been assessed only recently in 2
risk. The effect of genistein and daidzein was limited to hormone
studies in the United States but not yet in Europe.16,17 Both US
receptor-positive breast tumors. Additionally, a high amount of
studies, one with a prospective design,17 failed to ﬁnd a signiﬁcant
estimated enterodiol and enterolactone (mammalian lignans) is
association with breast cancer or an effect modiﬁcation by meno-
inversely related to premenopausal breast cancer risk.
pausal status or hormone receptor status of the tumor.TABLE II – DIETARY INTAKE (MEDIAN, 25%–75% PERCENTILE) OF SELECTED PHYTOESTROGENS AND ENERGY IN PREMENOPAUSAL
BREAST CANCER CASES (N ϭ 278) AND POPULATION-BASED CONTROLS (N ϭ 666)1
1Units are ␮g/day except for “Energy”, kcal/day.–2Mann-Whitney U-test.TABLE III – CONTRIBUTION OF FOOD GROUPS AND SUBGROUPS TO THE DIETARY INTAKE OF SELECTED PHYTOESTROGENS IN PREMENOPAUSAL
BREAST CANCER CASES AND CONTROLS (AVERAGE PERCENTAGE OF TOTAL INTAKE IN CASES/CONTROLS)
For the calculation of individual phytoestrogen intake, analytic
pumpkin seeds) and coffee. Potatoes, leafy vegetables, cabbages,
data from the literature were used, as described by other
onion/garlic, nuts/seeds, wine, tea and especially bread contributed
groups.15,38,50,51 With the exception of daidzein, the dietary intake
to the total matairesinol intake. The proportional contribution of
estimates for the different phytoestrogenic compounds in our sub-
food groups to the mammalian lignans is spread over a broad
jects are compatible with the results from a Dutch study in women
variety of foods like different kinds of vegetable, potatoes, fruits,
49 –70 years old participating in the Utrecht EPIC cohort.15 Data
nuts/seeds and bread, indicating differences in lignan sources.
on isoﬂavonoid intake in 4 European countries (Ireland, Italy, the
There are 2 major concerns over possible biases that may have
Netherlands, UK) also estimated an average intake of Ͻ1 mg/day,
affected the results. First, a case-control study design of nutritional
which was somewhat higher than that found in Germany.52 Studies
studies may suffer from recall bias in cases. This cannot be
from central Europe reporting lignan intake data are not available.
excluded for the present study. However, limited modiﬁcation of
Finnish data regarding dietary lignan intake vary widely but show
the diet over time has been indicated, also after a diagnosis of
distinctly lower secoisolariciresinol intake levels than we found
cancer. The type of food consumed can be regarded as a personal
here.50,53 Reported lignan and coumestrol intake values from 1 of
dietary preference, so intake levels of most persons are likely to be
3 studies in the United States are similar to our results,51 while
relatively stable over time.54 Zheng et al.47 observed that Ͼ90% of
others are not;16,17 however, isoﬂavonoid intake was higher in the
cases reported no appreciable dietary change during the time
period from initial cancer diagnosis to urine collection. Addition-
Differences in phytoestrogen intake between studies can be
ally, results from EPIC-Heidelberg, obtained with the same nutri-
explained by differing dietary habits but may also be affected by
tional assessment tool, were comparable to the present results in
differences in the phytoestrogen content of food (e.g., soy protein
terms of energy and nutrient intake ranges55 and, therefore, give
as an ingredient) or differences in the ability of the FFQ employed
some reassurance for the validity of the data. Further, dietary
to assess relevant food items for phytoestrogen intake. As shown
assessment was not the main topic of the original study project, so
in Table III, the important (Ͼ5% contribution) sources of daidzein
patients may not have been sensitized to nutrition. The descriptive
and genistein in the diet of our study population were soy sprouts,
data show few differences between the original study population
legumes, soy products, sauces and coffee (daidzein). Secoisolar-
and the subgroup with FFQ data; thus, selection bias can largely be
iciresinol is predominantly provided by nuts and seeds (ﬂaxseeds,
excluded as a source of error.29 Second, phytoestrogen data in-
TABLE IV – CRUDE AND ADJUSTED1 ORS AND 95% CIS FOR PREMENOPAUSAL BREAST CANCER RISK BY PHYTOESTROGEN INTAKE
1Adjusted for ﬁrst-degree family history of breast cancer, number of births, duration of breast-feeding, energy intake, BMI, alcohol
TABLE V – ADJUSTED1 ORS AND 95% CIS FOR PREMENOPAUSAL BREAST
food additives used in food manufacturing before 1995 were used
CANCER RISK BY COMBINATIONS OF LOW AND HIGH2
mainly for technologic reasons and pertain largely to soy protein
DIETARY INTAKE OF DAIDZEIN AND GENISTEIN AND OF
preparations (with widely varying isoﬂavonoid concentrations).
Regarding the lignans secoisolariciresinol and matairesinol, the
most important food sources were considered but there may be
other foods not analyzed so far. Several other plant lignans (e.g.,
pinoresinol, syringaresinol, lariciresinol) have been identiﬁed as
precursors of enterodiol and enterolactone,57 but their concentra-
tions in different foods are not available. This probably explains
why the food sources of secoisolariciresinol and matairesinol are
(0.46–1.10) (0.54–1.25) (0.36–0.83)
distinctly different from those of mammalian lignans (Table III).
The most critical point, however, may be the production of en-
Adjusted for ﬁrst-degree family history of breast cancer, number of
terodiol and enterolactone from ingested lignans in the human
births, duration of breast-feeding, energy intake, BMI, alcohol con-sumption and education.–2Low levels refer to 1st and 2nd quartiles,
intestine. The extent of lignan conversion in the gut depends
and high levels refer to 3rd and 4th quartiles.
largely on the quantity and composition of the gut microﬂora.18Here, we used data from Thompson et al.41 based on incubatingdifferent foods with freshly gained human feces. It has been
cluded in the database and used for intake calculations may be
reported that plasma enterolactone concentrations are decreased
incomplete for several reasons. In the case of isoﬂavonoids, the
for several months after antibiotic therapy.58 Additionally, gut
most important though unsolved question is the use of soy and soy
transit time and fat content of the diet appear to modulate the
components (e.g., soy protein) as food additives.56 The discussion
availability of mammalian lignans.18,59 Therefore, when calculat-
of possible health effects of soy was not yet popular during the
ing the available amount of mammalian lignans in the present
ﬁeld period of the study. Thus, it can be assumed that soy-derived
study, the reported high inter- and intraindividual differences in the
TABLE VI – ADJUSTED1 ORS AND 95% CIS FOR TOTAL DAIDZEIN AND GENISTEIN INTAKE AND PREMENOPAUSAL
BREAST CANCER RISK BY ESTROGEN AND PROGESTERONE RECEPTOR STATUS OF THE TUMOR
1Adjusted for ﬁrst-degree family history of breast cancer, number of births, duration of breast-feeding, energy intake, BMI, alcohol
production of mammalian lignans53,60 could not be taken into
monal proﬁle.64,65 This supports the view that a “healthy” diet
account. Isoﬂavonoids also undergo intestinal metabolism, and the
provides more bioavailable mammalian lignans but does not ex-
question of bioavailability of dietary isoﬂavonoids and their me-
clude the possibility that mammalian lignans exert their own
tabolites may also be important for understanding their health
effects.61,62 Equol is the intestinal isoﬂavonoid metabolite with the
In conclusion, our results give clear epidemiologic evidence for
strongest estrogenic activity, but it is produced in only about
a protective role against premenopausal breast cancer of a diet high
one-third of Caucasian people, depending largely on the intestinal
(albeit low compared to Asian populations) in daidzein, genistein
or matairesinol as well as estimated mammalian lignans enterodiol
Due to the difﬁculty in accounting for sources, metabolism and
and enterolactone. The association between isoﬂavonoid intake
bioavailability of dietary lignans, it is not surprising that the
and breast cancer risk was found only for hormone receptor-
association with breast cancer in our study was not the same for
positive tumors, while the effect of mammalian lignans was inde-
mammalian and plant lignans. Both approaches suffer from im-
pendent of receptor status. Whether phytoestrogens are the under-
precision: the lignan intake data do not reﬂect the bioavailable
lying causal agents of a favorable diet or a favorable gut microﬂora
fraction of lignan metabolites, and the enterodiol and enterolactone
or both in relation to reduced breast cancer risk remains to be
in vitro data used for calculation may be biased due to differences
in the physiologic gut ﬂora between subjects.
We previously reported from the same study population a sig-
niﬁcantly reduced risk of breast cancer associated with high con-sumption of vegetables.29 Since vegetables are sources of entero-
We are grateful to all participants for their help and patience as
diol and enterolactone, it cannot be excluded that the mammalian
well as to the many gynecologists and oncologists in the 38 clinics
lignan effect reﬂects a more healthy diet rich in vegetables. Dietary
of the study regions for allowing us to contact their patients. We
intervention studies have shown that a diet low in animal products
also thank Ms. U. Eilber for data coordination and management
and fat and high in complex carbohydrates, fruits and vegetables
and Ms. D. Zoller for programming and calculating dietary intake
increases enterolactone plasma concentrations and affects the hor-
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